Stabilized statin formulations

ABSTRACT

The present invention is directed to statin formulations having improved solubility and/or stability and methods for the same.

BACKGROUND OF THE INVENTION

It has been clear for several decades that elevated blood cholesterol isa major risk factor for coronary heart disease (CHD), and many studieshave shown that the risk of CHD events can be reduced by lipid-loweringtherapy. Prior to 1987, the lipid-lowering armamentarium was limitedessentially to diet modification to a low saturated fat and cholesteroldiet, the bile acid sequestrants (cholestyramine and colestipol),nicotinic acid (niacin), the fibrates and probucol. Unfortunately, allof these treatments have limited efficacy or tolerability, or both. Withthe introduction of lovastatin (MEVACOR®; see U.S. Pat. No.4,231,938)—the first inhibitor of HMG-CoA reductase to become availablefor prescription in 1987—physicians for the first time were able toobtain comparatively large reductions in plasma cholesterol with veryfew adverse effects.

The HMG CoA reductase inhibitors, commonly known are statins, aredivided into two groups: fermentation-derived and synthetic. In additionto the natural product lovastatin, there have been severalsemi-synthetic and totally synthetic HMG-CoA reductase inhibitorsapproved for prescription use, including simvastatin (ZOCOR®; see U.S.Pat. No. 4,444,784), pravastatin sodium salt (PRAVACHOL®; see U.S. Pat.No. 4,346,227), fluvastatin sodium salt (LESCOL®; see U.S. Pat. No.5,354,772), atorvastatin calcium salt (LIPITOR®; see U.S. Pat. No.5,273,995) and cerivastatin sodium salt (BAYCOL®; see U.S. Pat. No.5,177,080). Still other HMG-CoA reductase inhibitors are known to be indevelopment, for example pitavastatin also referred to as NK-104 (seePCT international publication number WO 97/23200); and rosuvastatin alsoknown as ZD-4522 (CRESTOR®; see U.S. Pat. No. 5,260,440, and Drugs ofthe Future, 1999, 24(5), pp. 511-513). The structural formulas of theseand additional HMG-CoA reductase inhibitors, are described at page 87 ofM. Yalpani, “Cholesterol Lowering Drugs”, Chemistry & Industry, pp.85-89 (5 Feb. 1996). The HMG-CoA reductase inhibitors described abovebelong to a structural class of compounds which contain a moiety whichcan exist as either a 3-hydroxy lactone ring or as the correspondingring opened dihydroxy open-acid, and are often referred to as “statins.”

U.S. Pat. No. 5,356,896 describes a pharmaceutical dosage formcomprising an HMG-CoA reductase inhibitor compound, e.g., fluvastatinsodium, which is stabilized against pH-related degradation by analkaline stabilizing medium capable of imparting a pH of at least 8 toan aqueous solution or dispersion of the composition. The '896 patentstates that the drug substance and the alkaline medium must be broughtinto intimate contacting association, preferably with an aqueous orother solvent-based preparative process, whereby “the drug substance andalkaline medium are blended together in the presence of minor amountsof, e.g., water, to provide particles containing the drug and alkalinesubstance in intimate admixture.” The resulting particles are dried andthen are blended with filler and remaining excipients, which were setaside to comprise an “external phase” of said particles, to result in acomposition suitable for encapsulation, tableting or the like.

In another embodiment described in the '896 Patent, a solvent-basedprocess is utilized to assist subsequent drying in a fluidized bed,whereby the drug substance and alkaline medium are wet granulated byknown techniques, i.e. blended in the moistened state, together with anamount of the filler material and the resulting granules, after drying,are combined with any remaining filler and other set-asides, e.g.,binder, lubricant, and can therefore be tableted, encapsulated, orotherwise shaped into a dosage form.

The '896 Patent states that to achieve extended shelf life of thecompositions, it is important “that the particles prepared bytrituration or wet granulation or other aqueous-based process besubstantially completely dried, i.e. to a weight loss on drying (L.O.D.)of not greater than 3%, and preferably not greater than 2%.” The '896patent also describes conventionally performed drying by tray drying orin a fluidized bed, preferably the latter with drying typicallyperformed at about 50.degree C. inlet temperature, and below 50% RH. The'896 Patent additionally describes an alternative preparative procedureto the above-described trituration or wet granulation techniques,wherein the drug substance and the alkaline stabilizing medium can beco-lyophilized, i.e. freeze-dried, from aqueous solution as a step insitu of the drug manufacturing process.

Most statins are relatively insoluble, and are considered by thoseskilled in the art to be unstable in solution, and therefore this classof drugs is manufactured in solid form. However, there are thosepatients who can not ingest, digest, or otherwise take medicationsorally and there is a need for the administration of medicationsintravenously. There are clinical indications that statins throughanti-inflammatory and possibly other mechanisms can reduce the incidenceof heart attacks, strokes, as well as other inflammatory mediatedconditions.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a stable product containinga statin that can be administered intravenously.

It is further object of the invention to provide a solid statinformulation which may be reconstituted in an aqueous solution suitablefor injection into mammals.

It is another object of the invention to provide lyophilized particlesof a statin and a solubilizing or complexing agent.

It is a further object to provide a method of preparing lyophilizedparticles of a statin and a solubilizing or complexing agent.

It is a further object to provide a method of treating human patientswith a statin using the formulations and methods described herein.

These objects and others are achieved by the present invention, which isrelated in part to a water-insoluble statin complexed with a sufficientamount of a pharmaceutically acceptable complexing agent in a solutionhaving a pH of from about 7 to about 9 to provide a solubilized statinconcentration of at least about 3.32 mg/ml. The invention is furtherrelated to a pharmaceutical formulation comprising an effective amountof the complexed statin as described above.

In certain embodiments, the solubilized statin concentration is fromabout 1 mg/ml to about 25 mg/ml. In certain preferred embodiments, thesolublized statin concentration is from about 5 mg/ml to about 15 mg/ml.In certain preferred embodiments, the solubilized statin concentrationis about 10 mg/ml.

In some embodiments, the statin may be selected from lovastatin,simvastatin, mevastatin, atorvastatin, cerivastatin and rivastatin.

In some embodiments, the complexing agent is a cyclodextrin. In certainpreferred embodiments, the complexing agent ishydroxy-propyl-β-cyclodextrin.

In some embodiments, the complexed statin is lyophilized.

The invention is also directed in part to solid particles comprising awater-insoluble statin which may be readily solubilized in an aqueoussolution suitable for injection into mammals, which are lyophilizedparticles comprising a pharmaceutically acceptable statin and asufficient amount of a pharmaceutically acceptable complexing agent.

The invention is further directed in part to lyophilized particlescomprising a water-insoluble statin and an effective amount of acomplexing agent to provide aqueous solubility to said statin and toprovide stability to the formulation when reconstituted in an aqueousenvironment.

In certain embodiments, the lyophilized particles are prepared by firstadding the water-insoluble statin to a complexing agent, after which thecombination is mixed. In some embodiments, the formulation is thenlyophilized to obtain lyophilized particles.

In certain preferred embodiments of the invention, the lyophilizedparticles comprising the water-insoluble statin and complexing agent arestable. By “stable”, it is meant that substantially no degradation ofthe lyophilized particles (the product) is observed after storage for 1month at 40° C. In preferred embodiments, the term “stable” with respectto the lyophilized particles comprising the water-insoluble statin andcomplexing agent means that there is less than about 0.1% degradationobserved) after storage for 1 month at 40° C.

In some embodiments of the present invention, the pH is adjusted to fromabout 7 to about 9 using a pharmaceutically acceptable buffer oralkalizing agent, with suitable alkalizing agents and buffers includingbut not limited to NaOH, KOH, triethylamine, meglumine, L-Arginine,sodium phosphate buffer (either sodium phosphate tribasic, sodiumphosphate dibasic, sodium phosphate monobasic, or o-phosphoric acid),sodium bicarbonate, and mixtures of any of the foregoing. In anembodiment of the invention, the lyophilized particles contain one ofthe following statins: lovastatin, simvastatin, pravastatin, mevastatin,fluvastatin, atorvastatin, rosuvastatin, cerivastatin and rivastatin.The lyophilized particles in certain embodiments may contain acyclodextrin as the complexing agent and in certain preferredembodiments, the cyclodextrin is hydroxy-propyl-β-cyclodextrin.

The invention is also directed in part to a method of preparinglyophilized particles comprising a pharmaceutically acceptable statinand a pharmaceutically acceptable complexing agent wherein the statin isadded to a mixture of the complexing agent and a suitable solvent afterwhich the combination is mixed. In certain embodiments, the pH is thenadjusted using a pharmaceutically acceptable buffer to a pH range offrom about 7 to about 9. The mixture may then be lyophilized to obtainlyophilized particles. The pharmaceutically acceptable statin ispreferably water-insoluble, and may be selected, e.g., from the groupconsisting of lovastatin, simvastatin, mevastatin, atorvastatin,cerivastatin and rivastatin. In certain embodiments, the complexingagent is a cyclodextrin.

Although in certain preferred embodiments the invention contemplates theuse of a statin that is water-insoluble, in further embodiments of theinvention the statin may be water insoluble or water soluble. Examplesof suitable water soluble statins include, but are not limited to,risuvastatin, fluvastatin and pravastatin.

Thus, in certain embodiments, the invention is directed to stableformulations of a soluble statin and methods for preparing the same. Insuch embodiments, the soluble statin(s) is stabilized via alyophilization step as described herein.

The invention is also directed to a method of preparing a stablepharmaceutical formulation comprising lyophilized particles of statin,wherein the statin is complexed with an effective amount of apharmaceutically acceptable complexing agent in an aqueous solution andthe pH is adjusted to from about 7 to about 9 prior to lyophilization.

In certain embodiments, the lyophilized particles are reconstituted inan effective amount of a pharmaceutically acceptable solution forinjection into a human patient. In certain further embodiments, thereconstituted lyophilized particles are injected into a human patient

The present invention is also directed in part to a method of treatmentcomprising (a) preparing lyophilized particles by adding a statin to amixture of a complexing agent and a suitable solvent and lyophilizingthe mixture to obtain lyophilized particles; (b) reconstituting thelyophilized particles in a pharmaceutically acceptable solution forinjection; and (c) administering a suitable quantity of the solution toprovide an effective amount of statin to a human patient in need oftreatment. In certain embodiments, the statin is administered in aneffective amount to lower the patient's lipid level and/or to produce adesired (therapeutically effective) anti-inflammatory effect or othertherapeutic effect.

In some embodiments, after the statin is added to the mixture of thecomplexing agent and the solvent, the mixture is vortexed and sonicatedand the pH of the mixture is adjusted to from about 7 to about 9 using apharmaceutically acceptable buffer.

In certain embodiments, the statin is selected from the group consistingof lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin,atorvastatin, rosuvastatin, cerivastatin and rivastatin and thecomplexing agent is a cyclodextrin.

In certain embodiments of the present invention, the complexing agentcomprises at least about 13.5% of the formulation.

It certain embodiments of the present invention, a solubilized statinconcentration of at least about 3.3 mg/ml is provided.

As mentioned above, objects of the present invention also comprisepharmaceutical compositions containing at least a compound of thepresent invention of formula (I) together with non toxic adjuvantsand/or carriers usually employed in the pharmaceutical field.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is shows a linear regression analysis of the minimum amount ofHPβ-CD needed to solubilize AS-Ca.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed in part to pharmaceutical formulationscomprising an effective amount of a pharmaceutically acceptable statincomplexed with a sufficient amount of a pharmaceutically acceptablecomplexing agent and method for preparing the same.

The present invention is further directed in part to formulations whichinclude a water-insoluble statin which is complexed with a sufficientamount of a pharmaceutically acceptable complexing agent to render thewater-insoluble statin soluble in an aqueous environment, whichformulation is also lyophilized in order to provide a stable formulationof a water-insoluble statin that can be solubilized in an aqueousenvironment.

Suitable water insoluble statins for use in the present inventioninclude, but are not limited to, lovastatin, simvastatin, mevastatin,atorvastatin, cerivastatin and rivastatin, pharamaceutically acceptablesalts thereof, and pharmaceutically acceptable complexes thereof. Theterm “water-insoluble” as it is used herein, means the USP definitionrange of very slightly soluble to insoluble (solubility not more than(NMT) 1:1000). In addition, the present invention is intended to covercompositions comprising other HMG-CoA reductase inhibitor compounds offormula I herein, including both the erythro racemate and itsconstituent isomers (i.e. the 3R,5S and 3S,5R isomers, preferably the3R,5S isomer).

These compounds are disclosed, e.g., in the following commonly assignedpatents, published patent applications and publications which are allhereby incorporated herein by reference: U.S. Pat. No. 4,739,073, andEP-A-114,027 (R=indolyl and derivatives thereof); EP-A-367,895(R=pyrimidinyl and derivatives thereof); U.S. Pat. No. 5,001,255(R=indenyl and derivatives thereof); U.S. Pat. No. 4,613,610(R=pyrazolyl and derivatives thereof); U.S. Pat. No. 4,851,427(R=pyrrolyl and derivatives thereof); U.S. Pat. Nos. 4,755,606 and4,808,607 (R=imidazolyl and derivatives thereof); U.S. Pat. No.4,751,235 (R=indolizinyl and derivatives thereof); U.S. Pat. No.4,939,159 (R=azaindolyl and derivatives thereof); U.S. Pat. No.4,822,799 (R=pyrazolopyridinyl and derivatives thereof); U.S. Pat. No.4,804,679 (R=naphthyl and derivatives thereof); U.S. Pat. No. 4,876,280(R=cyclohexyl and derivatives thereof); U.S. Pat. No. 4,829,081(R=thienyl and derivatives thereof); U.S. Pat. No. 4,927,851 (R=furyland derivatives thereof); U.S. Pat. No. 4,588,715 (R=phenylsilyl andderivatives thereof); and F. G. Kathawala, Medicinal Research Reviews,Vol. 11 (2), p. 121-146 (1991), and F. G. Kathawala, AtherosclerosisResearch—Review, June 1992, p. B73-B85.

Further compounds of formula I are disclosed e.g. in EP-A-304,063(R=quinolinyl and derivatives thereof); EP-A-330,057 and U.S. Pat. Nos.5,026,708 and 4,868,185 (R=pyrimidinyl and derivatives thereof);EP-A-324,347 (R=pyridazinyl and derivatives thereof); EP-A-300,278(R=pyrrolyl or derivatives thereof); and U.S. Pat. No. 5,013,749(R=imidazolyl and derivatives thereof), hereby incorporated byreference.

“Complexing agents” are small molecular weight molecules which can forman inclusion complex and after suitable curing time, can solubilize thedrug and may impart additional stability to the drug. Accordingly, forpurposes of the present invention, the term “complexing agent” is meantto encompass agents that complex and/or solubilize a water-insolublestatin. In certain embodiments of the present invention, thepharmaceutically acceptable complexing agent is a dextrin. Othersuitable dextrins include cyclodextrins such ashydroxy-propyl-β-cyclodextrin and sulfobutyl-ether-β-cyclodextrin.Additional cyclodextrins could include alpha-cyclodextrins,beta-cyclodextrins, gamma-cyclodextrins, beta-cyclodextrin ethercomprising one or more hydroxybutyl sulfonate moieties and cyclodextrinsas described in U.S. Pat. No. 6,610,671 or U.S. Pat. No. 6,566,347 (bothof which are incorporated by reference).

Additional complexing agents include, but are not limited to, the groupconsisting of phenol, phenolic salts, aromatic acids and esters,carboxylic acids and salts and esters thereof, inorganic acids and basesand amino acids and esters and salts thereof: methylparaben,propylparaben, potassium methylparaben, parabens, ascorbic acid and itsderivatives, methyl anthranilate, salicylic acid, acetosalicyclic acid,tocopherol, organic acids, carboxylic acids, aromatic acids, aromaticesters, acid salts of amino acids, benzaldehyde, cnnimaldehyde,imidazole, menthol, thiophenol, m-aminobenzoic acid, anthranilic acid,picolinic acids and alkyl esters thereof, toluidides, sodium benzoate,sodium metabisulphite, malic acid, isoascorbic acid, citric acid,tartaric acid, sodium sulphite, sodium bisulphate, water- andfat-soluble derivatives of tocopherol, sulphites, bisulphites andhydrogen sulphites, propyl/gallate, nordihydroguaiaretic acid,phosphoric acids, sorbic and benzoic acids, methylparaben, sodiummethylparaben, para-aminobenzoic acid and esters, sorbic and benzoicacids, 2,6-di-t-butyl-alpha-dimethylamino-p-cresol, t-butylhydroquinone,di-t-amylhydroquinone, di-t-butylhydroquinone, butylhydroxytoluene(BHT), butylhydroxyanisole (BHA), pyrocatechol, pyrogallol, esters,isomeric compounds thereof, pharmaceutically acceptable salts thereof,and mixtures of any of the foregoing.

In certain embodiments of the present invention, the complexing agentcomprises at least 13.5% of the formulation.

In certain embodiments, the statin and complexing agent are combined byadding the statin to a mixture of the complexing agent in an aqueoussolution. The aqueous solution may be a suitable pharmaceuticallyacceptable solvent, such as water for injection or Na2HPO4 in water forinjection. After complexation of the statin, the pH may be adjusted to apH of over 6.5. In certain embodiments the pH is modified to from about7 to about 9. Suitable agents for modifying the pH include sodiumphosphate buffer (either sodium phosphate tribasic (Na₃PO₄) or sodiumphosphate dibasic (Na₂HPO₄)), o-phosphoric acid, NaOH and L-Arginine(L-dArg).

In certain embodiments of the present invention, the mixture is mixed bya variety of means including vortexing and sonication. The mixing may berepeated more than 1 time. It may be desirable to adjust the volume ofsolution and/or its pH between each mixing step.

In an embodiment of the invention, the mixture of statin and complexingagent is lyophilized.

The stability of the formulations of the present invention is determinedby any suitable method known to those of skill in the art. An example ofa suitable method of testing stability is using high performance liquidchromatography or other common analytical technology.

The daily dose of active ingredient can administered as a single dose.The dosage regimen and administration frequency for treating thementioned diseases with the compound of the invention and/or with thepharmaceutical compositions of the present invention will be selected inaccordance with a variety of factors, including for example age, bodyweight, sex and medical condition of the patient as well as severity ofthe disease, pharmacological considerations, half-life of the drug, andeventual concomitant therapy with other drugs. In some instances, dosagelevels below or above the aforesaid range and/or more frequent may beadequate, and this logically will be within the judgment of thephysician and will depend on the disease state.

Where the active ingredient is atorvastatin, the total daily dose may bein amounts preferably from 10 to 80 mg but may be lower or higher asrequired. The preferable starting dose of atorvastatin is 10 or 20 mgonce daily, though if needed large LDL-C reduction may start at 40 mgonce daily. The pediatric starting dose of atorvastatin is 10 mg oncedaily with a maximum does of 20 mg once daily. For HMG CoA reductaseinhibitors other than atorvastatin, it is within the understanding ofone of skill in the art to calculate conversion dosing based on thepreferable dosing for atorvastatin. In addition, conversion tables forsuch calculation are readily available for many of the known statins.

The compounds of the invention may be administered orally, parenterally,rectally or topically, by inhalation or aerosol, in formulationseventually containing conventional non-toxic pharmaceutically acceptablecarriers, adjuvants and vehicles as desired. Topical administration mayalso involve the use of transdermal administration such as transdermalpatches or iontophoresis devices. The term “parenteral” as used herein,includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

Injectable preparations, for example sterile injectable aqueous oroleaginous suspensions may be formulated according to known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent.Among the acceptable vehicles and solvents are water, Ringer's solutionand isotonic sodium chloride. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono ordiglycerides, in addition fatty acids such as oleic acid find use in thepreparation of injectables.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring and thelike.

Newer statin nitroderivatives in addition to lowering lipid, possessenhanced anti-inflammatory, antiplatelet and antithrombotic effects ascompared to native statins. Moreover, they can be effective also in theother pathologies such as acute coronary syndromes, stroke, peripheralvascular diseases such as peripheral ischemia, all disorders associatedwith endothelial dysfunctions such as vascular complications in diabeticpatients and atherosclerosis, neurodegenerative diseases such asAlzheimer's disease (AD) and Parkinson's disease (PD), autoimmunediseases such as multiple sclerosis.

In alternative embodiments of the treatment methods described herein, apharmaceutical formulation comprising a statin is administered to apatient via an injection method. In such embodiments the pharmaceuticalformulation of the statin is a formulation suitable for administrationto a patient via the injection method. Suitable injection methodsinclude, in addition to intravenous injection, intraarterial infusion,intramuscular injection, transdermal injection, and subcutaneousinjection.

Suitable carriers for intravenous administration include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingsolubilizing agents, such as glucose, polyethylene glycol, andpolypropylene glycol and mixtures thereof.

The formulation may include an aqueous vehicle. Aqueous vehiclesinclude, by way of example and without limitation, Sodium ChlorideInjection, Ringers Injection, Isotonic Dextrose Injection, Sterile WaterInjection, Dextrose, and Lactated Ringers Injection. Nonaqueousparenteral vehicles include, by way of example and without limitation,fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil andpeanut oil. Antimicrobial agents in bacteriostatic or fungistaticconcentrations must be added to parenteral preparations packaged inmultiple dose containers which include phenols or cresols, mercurials,benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acidesters, thimerosal, benzalkonium chloride and benzethonium chloride.Isotonic agents include, by way of example and without limitation,sodium chloride and dextrose. Buffers include phosphate and citrate.Antioxidants include sodium bisulfate. Local anesthetics includeprocaine hydrochloride. Suspending and dispersing agents include sodiumcarboxymethylcelluose, hydroxypropyl methylcellulose andpolyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN®80) A sequestering or chelating agent of metal ions include EDTA.]Pharmaceutical carriers also include, by way of example and withoutlimitation, ethyl alcohol, polyethylene glycol and propylene glycol forwater miscible vehicles and sodium hydroxide, hydrochloric acid, citricacid or lactic acid for pH adjustment.

Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,such as more than 1% w/w of the statin. In certain embodiments, thesolubilized statin concentration of the formulation will be at leastabout 3.3 mg/ml.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

In certain embodiments, the invention is directed to a method ofreducing the risk of MI, stroke, revascularization procedures, angina inpatients without CHD but with multiple risk factors, reducing the riskof MI and stroke in patients with type 2 diabetes without CHD, but withmultiple risk factors, reducing the risk of non-fatal MI, fatal andnon-fatal stroke, revascularization procedures, hospitalization for CHF,and angina in patients with CHD, reducing elevated total-cholesterol,LDL□cholesterol, apolipoprotein-B, and triglyceride levels in patientswith primary hyperlipidemia (heterozygous familial and nonfamilial andmixed dyslipidemia), reducing elevated triglyceride levels in patientswith hypertriglyceridemia and primary dysbetalipoproteinemia, reducingtotal cholesterol and LDL-cholesterol in patients with homozygousfamilial hypercholesterolemia, reducing elevated total-C, LDL-C, and apoB levels in boys and postmenarchal girls, 10 to 17 years of age, withheterozygous familial hypercholesterolemia after failing an adequatetrial of diet therapy, mixed dyslipidaemia; and heterozygous familialhyperlipidemia, homozygous familial hypercholesterolaemia as an adjunctto other lipid-lowering treatments (e.g. LDL apheresis) or if suchtreatments are unavailable.

Particularly, the non-statin pharmaceutical drugs for use in thepractice of this invention are any of the PPAR receptor agonists,including those that are selective for one PPAR receptor sub-type aswell as those that are active for two or more receptor sub-types. Moreparticularly, the non-statin pharmaceutical drugs are PPAR alphaagonists such as the fibric acid derivatives; PPAR gamma agonists; anddual PPAR alpha/gamma agonists, i.e., those having dual activity forboth the alpha and the gamma receptor sub-types.

When a statin and a non-statin are referred to as competitively bindingto an enzyme or enzyme isoform (i.e., isozyme), it means both the statinand the non-statin bind to the same enzyme or isozyme. An adversepharmacokinetic drug interaction is intended to mean an in vivointeraction between a statin and a co-administered non-statinpharmaceutical drug in a mammal, particularly a human, which raises theplasma level of active open-acid statin above the level it would be atif the statin was administered alone, i.e., absent the co-administerednon-statin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLES 1-3

Examples 1-3 compare solubilization methods to evaluate the affect ofpH, buffer strength, and different mixing methods. In Example 1, sampleswere made in 100 mM sodium phosphate dibasic (Na₂HPO₄) at pH 5.5, 6.5,7.5, and 8.5. The samples were only vortexed. In Example 2, samples weremade in 100 mM Na2HPO4 at pH 5.5, 6.5, 7.5, and 8.5 and then bothvortexed and sonicated. In Example 3, samples were made in either 25 or50 mM Na₂HPO₄ at either pH 7.5 or 8.5.

EXAMPLE 1

10 mg of atorvastatin calcium trihydrate (“AS-Ca”) was added toapproximately 0.9 mls of a solution containing 0.8 mls of 34.7%hydroxy-propyl-β-cyclodextrin (“HPβ-CD”) and 0.1 ml of 1 M Na2HPO4 inultrapure water and then vortexed at top speed for 5 minutes. The pH ofthe samples were then adjusted to pH 5.5, 6.5, 7.5, or 8.5 with 0.85%o-phosphoric acid or 0.1 M NaOH. Each sample was vortexed, and thenultra-pure water was added to q.s. to 1.0 mls, after which the samplewas filtered through a 0.45 μm nylon filter, and analyzed by HPLC (seeTable 1).

EXAMPLE 2

The formulations of Example 2 were prepared in the same manner as thoseof Example 1, except that after vortexing, the formulations of Example 2were additionally sonicated. The samples were analyzed by HPLC (SeeTable 1).

EXAMPLE 3

10 mg of AS-Ca was added to approximately 0.9 mls of a solutioncontaining 0.8 mls of 34.7% HPβ-CD and either 0.025 or 0.050 ml of 1 MNa₂HPO₄in ultrapure water and then vortexed for 5 min. The pH of thesamples was adjusted to either 7.5 or 8.5 using 0.1 M NaOH, and thenultrapure water was added q.s. to 1 mL, after which the samples werevortexed for 5 min, filtered, and then analyzed by HPLC (See Table 1).

TABLE 1 Na2HPO4 Solubilized concentration Mixing Atorvastatin ExampleSample pH (mM) Method (mg/ml) 1 5.5 100 Vortex 3.32 6.5 100 Vortex 8.427.5 100 Vortex 8.89 8.5 100 Vortex 7.97 2 5.5 100 Sonication 3.27 6.5100 Sonication 9.21 7.5 100 Sonication 9.06 8.5 100 Sonication 9.26 37.5 25 Vortex 8.34 7.5 50 Vortex 8.58 8.5 25 Vortex 9.26 8.5 50 Vortex9.65Results: The solubility of AS-Ca was greatly improved by adjusting thepH to 6.5 and above.

EXAMPLES 4-5

The solubility of AS-Ca in formulations using different methods of pHadjustment are compared in Examples 4 and 5 to evaluate complexationefficiency. In Example 4, the pH was adjusted to 9 using NaOH and thenphosphoric acid was added to reduce the pH back to pH 7.0-8.5. InExample 5, the pH was adjusted to a pH between 7.0-8.5 with either 0.85%o-phosphoric acid or 0.1 M NaOH.

EXAMPLE 4

Mixtures of 20 mg/ml of AS-Ca were prepared by adding 20 mg AS-Ca toapproximately 0.8 mL mixture of 27.78% HPβ-CD, 50 mM Na₂HPO₄, andultrapure water and then phosphoric acid and/or NaOH were added to q.s.to 1 ml. The mixture of 20 mg/ml AS-Ca was then vortexed for 5 min andsonicated for 15 minutes.

The pH of the samples were adjusted to pH 9.0 using 0.1 M NaOH afterwhich the pH was further adjusted to pH 7.0, 7.5, 8.0, or 8.5 with 0.85%o-phosphoric acid. Each sample was vortexed, q.s. to 1.0 mls withultra-pure water, filtered, and then analyzed by HPLC.

EXAMPLE 5

Mixtures of 20 mg/ml of AS-Ca was prepared by adding 20 mg AS-Ca toapproximately 0.8 ml mixture of 27.78% HPβ-CD, 50 mM Na2HPO4, andultrapure water and then phosphoric acid and/or NaOH were added to q.s.to 1 ml. The mixture of 20 mg/ml AS-Ca was then vortexed for 5 min andsonicated for 15 minutes.

The pH of the samples were adjusted to pH 7.0, 7.5, 8.0, or 8.5 witheither 0.85% o-phosphoric acid or 0.1 M NaOH. Each sample was vortexed,q.s. to 1.0 mls with ultra-pure water, filtered, and then analyzed byHPLC.

Results: Results are provided below in Table 2.

TABLE 2 Atorvastatin Concentration Example Sample pH mg/ml 4 7.0 18.457.5 17.90 8.0 19.62 8.5 18.51 5 7.0 16.93 7.5 17.83 8.0 18.97 8.5 19.44

EXAMPLE 6

The relationship between AS-Ca and HPβ-CD was examined by evaluating thecomplexation efficiency of different concentrations of HPβ-CD. A stocksolution of HPβ-CD was first prepared at 34.7% and serially diluted to0.5375% HPβ-CD.

Samples were prepared by adding 20 mg of AS-Ca to 0.8 mls of HPβ-CDdilutions (final concentration in 1 ml from 27.78% to 0.5375% HPβ-CD)and 0.05 ml of 1 M Na₂HPO₄. Each sample was adjusted to pH 9.0 with 0.1M NaOH and then the samples were vortexed for 5 minutes and thensonicated for 15 minutes. The pH was then adjusted to either 7.5 or 8.5with 0.85% o-phosphoric acid. The samples were vortexed and sonicatedagain, then filtered and analyzed by HPLC (see Table 3).

-   Results: The solubility of AS-Ca increased linearly with HPβ-CD    concentration. Linear regression analysis showed that the minimum    amount of HPβ-CD needed to solubilize AS-Ca at 10 mg/ml was 14.4% at    pH 7.5 and 13.5% at pH 8.5. (See FIG. 1).

TABLE 3 pH 8.5 pH 7.5 Atorvastatin Atorvastatin Concentration HPβ-CD (%)(mg/ml) HPβ-CD (%) (mg/ml) 27.78 19.48 27.78 19.72 13.89 10.01 13.8912.42 6.94 5.13 6.94 5.54 3.47 1.38 3.47 1.58 1.74 0.43 1.74 0.52 0.870.34 0.87 0.215

EXAMPLE 7

Forced degradation and preliminary stability studies showed that AS-Casolubilized with HPβ-CD did not exhibit good stability. Therefore,lyophilization was evaluated using a manifold freeze dryer to determinewhether stability could be improved by this method.

100 mg of AS-Ca was added to approximately 9 mls of a solutioncontaining 5.333 ml of 37.5% HPβ-CD and 0.5 ml of 1 M Na₂HPO₄. Thesample was vortexed for 5 minutes and then sonicated for 15 minutes. ThepH was then adjusted to 9.0 using 0.1M NaOH, after which the sample wasagain vortexed and sonicated.

Next, the pH of the sample was adjusted to pH 8.5 using 0.85%o-phosphoric acid followed by vortexing and sonication. The sample wasq.s. to 10 mls with NaOH and 1% phosphoric acid to a pH of 8.47,filtered and then analyzed by HPLC. The final formulation contained 10mg/ml AS-Ca2+, 20% HPβ-CD, 50 mM Na₂HPO₄, q.s. with 0.1 M NaOH and 1%phosphoric acid at a pH of 8.47.

Results: AS-Ca solubilized with HPβ-CD was lyophilized and then placedon stability at 40° C. for 1 month alongside a control solution of thesame mixture. Lyophilized AS-Ca degraded ˜3.5% and AS-Ca in solutiondegraded ˜15.5%. Therefore, the sample was not stable in solution orwhen lyophilized using a manifold freeze-dryer.

EXAMPLE 8

Atorvastatin was prepared as described in example 6, except it wasprepared at 20 mg/mL in 30% HPβ-CD in 100 mM sodium phosphate adjustedto a final pH of 8.5. The sample was then diluted 1:1 into an 8% sucrosesolution and transferred to 5 mL vials. The vials were capped withlyophilization stoppers.

The samples were frozen at −40° C. on a shelf freezer followed by a 60min hold. After the freezing step, the condenser was adjusted to −85° C.and held at that temperature throughout the run. The pressure wasapproximately 20 mtorr. The shelf temperature was then adjusted to −20°C., −10° C., and 0° C. and held for 180 min at each temperature whilemaintaining vaccuum. Next the temperature was ramped to 10° C. and thento 20° C. (240 minutes for each step). The temperature was then adjustedto 40° C. and held until the vacuum was released and vials removed andvisually inspected.

-   Results: When AS-Ca was solubilized with HPβ-CD and then lyophilized    using a shelf freeze dryer, no degradation (less than 0.1%) was    observed after storage for 1 month at 40° C. Although not wishing to    be bound by this theory, the enhanced stability is likely due to    rapid removal of water and low residual moisture levels obtained by    conditions of the lyophilization cycle.

EXAMPLES 9 AND 10

In Examples 9 and 10, Sulfobutyl-ether-β-cyclodextrin (“SBE-β-CD”) wasevaluated as a possible alternative to HPβ-CD by means of AS-Cacomplexation with SBE-β-CD. The effect of sodium phosphate salt versusultrapure water on the solubilization of AS-Ca with SBE-β-CD atdifferent pH was also evaluated.

EXAMPLE 9

In Example 9, AS-Ca complexation with SBE-β-CD was in sodium phosphatebuffers with different pH values. 20 mg/ml of AS-Ca was added into27.78% SBE-β-CD in 50-100 mM of either NaH₂PO₄ (pH 2.13 samples) orNa₂HPO₄ (pH 7.07, 8.75, and 11.75 samples). Each sample was thenvortexed and sonicated, after which the pH was adjusted to 2.13 and 7.07using 0.85% o-phosphoric acid or 8.75 and 11.50 with 0.1 M NaOH. Thesamples were then vortexed, sonicated, q.s. to 1.0 ml with ultrapurewater, and then filtered and analyzed by HPLC (see Table 4 below).

-   Results: The solubility of AS-Ca was roughly 10-fold lower when    complexed with SBE-β-CD than when complexed with HPβ-CD.

TABLE 4 Atorvastatin Sample pH (mg/ml) 2.13 0.228 7.07 1.993 8.75 1.26711.75 1.927

EXAMPLE 10

In Example 10, the AS-Ca complexation with SBE-β-CD was in ultrapurewater to investigate the impact of phosphate buffer salt on the abilityof SBE-β-CD to complex AS-Ca. Based on the solubility findings ofExample 8, the formulation was tried at neutral and basic pH.

Neutral pH: 20 mg/ml AS-Ca was added to 27.78% SBE-β-CD in ultrapurewater. The sample was vortexed and sonicated, after which the pHdetermined to be 7.09. The sample was then q.s. to 1.0 ml with ultrapurewater, filtered, and analyzed by HPLC. (See Table 5)

Basic pH: 20 mg/ml AS-Ca was added to 27.78% SBE-β-CD in approximately0.8 mL ultrapure water. The sample was processed as described above,except the pH was adjusted to 11.0 using 0.1 M NaOH and q.s. to 1.0 mL.

-   Results: Phosphate buffer does not appear to have a significant    effect on the solubility of atorvastatin combined with SBE-β-CD.

TABLE 5 Atorvastatin Sample pH (mg/ml) 7.09 1.392 11.0 1.927

EXAMPLE 11

Additional AS-Ca formulations were prepared using other cyclodextrins,including γ-cyclodextrin and hydroxyl-propyl-γ-cyclodextrin. Thesolubility was found to be less than that achieved with SBE-β-CD orHPβ-CD.

EXAMPLE 12

In Example 12, the AS-Ca was solubilized with a co-solvent to evaluateco-solvent/aqueous solubility as a function of pH. The pH dependence onpropylene glycol and ethanol co-solvent formulations was, in particular,examined.

10 mg of AS-Ca was added to approximately 0.9 mls of solution containing4.0 mls of propylene glycol and 1.0 ml of ethanol in ultrapure water.The sample was vortexed and sonicated as described above, then adjustedto pH 9.0 with 0.1 M NaOH. The samples were vortexed and sonicated againand then the pH was adjusted to pH 7.0, 7.5, 8.0, or 8.5 with 0.85%o-phosphoric acid or left at pH 9.0. The samples were vortexed,sonicated, the sample was q.s. to 1.0 ml with ultrapure water, filtered,and then analyzed by HPLC. (See Table 6)

-   Results: There was no difference in solubility when pH was varied    from 7.0 to 9.0. However, when the samples were diluted 1:1 into    water, the samples adjusted to pH 7.5 and 8.0 precipitated.    Therefore, a pH >8.0 is preferable when the product is to be diluted    in aqueous vehicles.

TABLE 6 Atorvastatin Sample pH (mg/ml) 9.00 9.280 8.50 9.506 8.00 8.6417.50 9.361 7.00 8.876

EXAMPLE 13

Example 13 examines the amount of solvent needed to solubilize AS-Ca byevaluating co-solvent/aqueous solubility as a function of co-solventproportions.

10 mg of atorvastatin calcium was added to approximately 0.9 mls ofsolution containing the following solvent ratios in ultrapure water:

-   -   a. 40/10, 4.0 mls of propylene glycol and 1.0 ml of ethanol    -   b. 30/10, 3.0 mls of propylene glycol and 1.0 ml of ethanol    -   c. 20/10, 2.0 mls of propylene glycol and 1.0 ml of ethanol    -   d. 40/5, 4.0 mls of propylene glycol and 0.5 ml of ethanol    -   e. 40/0, 4.0 mls of propylene glycol and 0.0 ml of ethanol

The samples were each vortexed for 5 min and then sonicated for 15minutes. The samples were first adjusted to pH 9.00 with 0.1 M NaOH,vortexed, and then sonicated. The pH of the samples was adjusted to pH8.50 with 0.85% o-phosphoric acid and the samples were again vortexedand sonicated. The samples were q.s. to 1.0 ml with ultrapure water,filtered, and then analyzed by HPLC (see Table 7).

-   Results: The best solubility was achieved with 40% propylene glycol    (v/v) and 10% ethanol (v/v). Forced degradation studies showed that    anything less than 40% propylene glycol and 10% ethanol resulted in    atorvastatin precipitation when diluted with normal saline.

TABLE 7 Concentration Sample PG/EtOH mg/ml A 40/10 21.27 B 30/10 17.87 C20/10 16.80 D 40/5  18.11 E 40/0  16.06

EXAMPLE 14

Forced degradation studies also showed significant degradation withco-solvent/aqueous vehicles. Therefore, non-aqueous co-solvents wereexamined.

10 mg of AS-Ca was added to a 1.0 ml of propylene glycol and ethanol(4/1). The samples were vortexed and then the pH of the sample wasadjusted to pH 11.0 with 0.1 M NaOH. The samples were then filtered, andanalyzed by HPLC.

-   Results: The sample was completely soluble (9.34 mg/ml). When the    solution was diluted 1:3 in saline, it precipitated.

EXAMPLE 15

Forced degradation analysis showed that AS-Ca was relatively stable athigh pH. Therefore, the pH was adjusted with L-Arginine (L-Arg), NaOH,or sodium phosphate buffer (either sodium phosphate tribasic (Na₃PO₄) orNa₂HPO₄).

20 mg of AS-Ca was added to approximately 0.8 mL ml of the solutions 1-5below, followed by vortexing and sonication. The pH of the samples wasadjusted to a basic pH followed by q.s. to a volume of 1 mL withultrapure water, vortexing, sonication, filtering, and HPLC analysis.

Solution 1: 20 mg of AS-Ca was added to water containing 16.54 mM L-Arg(1:1 Atorvastatin:L-Arg molar ratio). The pH was adjusted to 10.98 with10% L-Arg. The resulting AS-Ca concentration was 0.46 mg/ml.

Solution 2: 20 mg of AS-Ca was added to water and the pH was adjusted to11.68 with 0.1 M NaOH. The resulting AS-Ca concentration was 0.222mg/ml.

Solution 3: 20 mg AS-Ca was added to water containing 0.1 M Na₃PO₄. Themeasured pH was 11.75. The resulting AS-Ca concentration was 0.46 mg/ml.

Solution 4: 20 mg AS-Ca was added to water containing 0.1 M Na₃PO₄ and16.54 mM L-Arg. The measured pH was pH 10.79. The resulting AS-Caconcentration was 3.17 mg/ml.

Solution 5: 20 mg AS-Ca was added to water containing 0.1 M Na₂HPO₄ and16.54 mM L-Arg. The measured pH was 10.79. The resulting AS-Caconcentration was 3.43 mg/ml.

-   Results: The solubility of AS-Ca in basic solutions with no HPβ-CD    varied from ˜0.2 to 3.5 mg/mL. Using 16.54 mM L-Arg with either 0.1    M Na₃PO₄ or Na₂HPO₄ resulted in AS-Ca concentrations of >3 mg/mL.    Therefore using a combination of L-Arg with either Na₃PO₄ or Na₂HPO₄    also provides adequate solubility for preparation of AS-Ca in    solutions.

EXAMPLES 16 -19

Atorvastatin free acid solubility (“AS”) was examined as an alternativeto the calcium trihydrate version.

EXAMPLE 16

The solubility of AS with complexation was evaluated by examining thesolubility of AS-Ca in 27.78% of either HPβ-CD or SBE-β-CD in 50 mMNa₂HPO₄ adjusted to pH 10.35 and 10.65 using 0.1 M NaOH respectively.The same methods of solubilization were used as example 4.

-   Results: AS solubility was 13.3 mg/ml with HPβ-CD and 1.96 mg/ml    with SBE-β-CD complexation.

EXAMPLE 17

In Example 17, solubilization of AS with a co-solvent was evaluated bytesting whether AS could be dissolved in a non-aqueous co-solvent athigh pH and then diluted into saline, without precipitation. Previousdata (example 13) showed that the AS-Ca would precipitate when preparedin non-aqueous co-solvents and then diluted into saline.

20 mg AS (20 mg) was added to approximately 0.9 mls of propylene glycoland ethanol (4/1 ratio) co-solvent. The measured pH was 6.64. The pH wasadjusted to pH 11.0 with 0.1 M NaOH, q.s. to a volume of 1 mL withultrapure water. The sample was then vortexed, filtered, after which itwas analyzed by HPLC.

-   Results: The sample degraded rapidly (approximately 50% in 2 hours).    The peak area was conserved between atorvastatin and its degradation    peaks. The AS concentration was estimated to be about 20 mg/ml.

EXAMPLE 18

In Example 18, AS solubility in either 100% propylene glycol or 100%ethanol similar to the propylene glycol/ethanol (4/1) solvent using thesame methods of solubilization described above. Atorvastatin free acidwas completely soluble in either 100% propylene glycol or 100% ethanolsimilar to the propylene glycol/ethanol (4/1) solvent. Both solutionsprecipitated when diluted 1:1 with saline and were found to be unstable.

EXAMPLE 19

In Example 19, the solubility of AS was examined by adjusting to a highpH with L-Arginine (L-Arg), NaOH, or sodium phosphate buffer (either(Na₃PO₄) or Na₂HPO₄).

20 mg of AS was added to approximately 0.8 ml of the solutions belowfollowed by vortexing and sonication. The pH of the samples was adjustedto a basic pH, followed by q.s. to a volume of 1 mL with ultrapurewater. The sample was then vortexed, sonicated, filtered, and HPLCanalysis was conducted.

Sample 1: 20 mg AS was added to a solution of 16.54 mM L-Arg. Themeasured pH was 10.35, which was then adjusted to 10.71 with L-Arg. Theresulting AS-Ca concentration was 1.91 mg/ml.

Sample 2: 20 mg AS was added to ultrapure water and the pH was adjustedto 11.15 with 0.1 M NaOH. The resulting AS concentration was 0.06 mg/ml.

Sample 3: 20 mg AS was added to 16.54 mM L-Arg and 0.1M Na3PO4. Themeasured pH was 11.42. The resulting AS concentration was 0.44 mg/ml

Sample 4: 20 mg AS was added to 0.05 M Na₃PO₄. The measured pH was11.55. The resulting AS concentration was <LOQ (Limit of Quantitation).

-   Results: The solubility of AS in basic solutions using Na₃PO₄, NaOH,    or Na₃PO₄ and L-Arg was <1.0 mg/mL. ASs solubility was 1.91 mg/mL    when using L-Arg alone. Therefore using L-Arg at an elevated pH    provides an adequate solubility.

CONCLUSION

Non-aqueous formulations composed of propylene glycol/ethanol (4/1) atpH 11.0 were examined to decrease the observed degradation. However,that formulation precipitated when diluted 1:1 into normal saline. Toimprove stability, preliminary lyophilized formulations of AS-Ca withHPβ-CD were examined. Initial stability of this formulation showedimproved stability over leaving the sample in solution.

It will be readily apparent to one of ordinary skill in the relevantarts that other suitable modifications and adaptations to the methodsand applications described herein are suitable and may be made withoutdeparting from the scope of the invention or any embodiment thereof.While the invention has been described in connection with certainembodiments, it is not intended to limit the invention to the particularforms set forth, but on the contrary, it is intended to cover suchalternatives, modifications and equivalents as may be included withinthe spirit and scope of the invention as defined by the followingclaims.

1. A liquid pharmaceutical formulation comprising an effective amount of a pharmaceutically acceptable water insoluble statin complexed with a sufficient amount of a pharmaceutically acceptable complexing agent in an aqueous solution having a pH of from about 7 to about 9 to provide a solubilized statin concentration of at least about 3.32 mg/ml.
 2. The formulation of claim 1, wherein the complexed statin is lyophilized.
 3. The formulation of claim 1, wherein the statin is selected from the group consisting of lovastatin, simvastatin, mevastatin, atorvastatin, cerivastatin and rivastatin.
 4. The formulation of claim 1, wherein the complexing agent is a cyclodextrin.
 5. The formulation of claim 4, wherein the cyclodextrin is hydroxy-propyl-β-cyclodextrin.
 6. The formulation of claim 1, wherein the solubilized statin concentration is from about 1 mg/ml to about 25 mg/ml.
 7. The formulation claim 1, wherein the complexing agent comprises at least 13.5% of the formulation.
 8. The formulation of claim 6, wherein the solubilized statin concentration is from about 5 to about 15 mg/ml.
 9. The formulation of claim 6, wherein the solubilized statin concentration is about 10 mg/ml.
 10. The formulation of claim 1, wherein the statin is selected from the group consisting of lovastatin, simvastatin, mevastatin, atorvastatin, cerivastatin and rivastatin and the complexing agent is a cyclodextrin.
 11. Lyophilized particles comprising a pharmaceutically acceptable water insoluble statin and a sufficient amount of a pharmaceutically acceptable complexing agent to render the statin water-soluble when the lyophilized particles are reconstituted in a pharmaceutically acceptable solution for injection.
 12. The lyophilized particles of claim 11, which do not substantially degrade after storage for 1 month at 40° C.
 13. The lyophilized particles of claim 12, which degrade less than about 0.1% after storage for 1 month at 40° C.
 14. The lyophilized particles of claim 12, wherein the statin is selected from the group consisting of lovastatin, simvastatin, mevastatin, atorvastatin, cerivastatin and rivastatin.
 15. The lyophilized particles of claim 12, wherein the complexing agent is a cyclodextrin.
 16. The lyophilized particles of claim 12, wherein the cyclodextrin is Hydroxy-propyl-β-cyclodextrin.
 17. The lyophilized particles of claim 12, which are reconstituted to a statin concentration from about 1 mg/ml to about 25 mg/ml.
 18. The formulation of claim 12, which are reconstituted to a statin concentration from about 5 to about 15 mg/ml.
 19. The formulation of claim 12, which are reconstituted to a statin concentration of about 10 mg/ml.
 20. A method of preparing lyophilized particles comprising a pharmaceutically acceptable statin and a pharmaceutically acceptable complexing agent comprising: (a) adding a water insoluble statin to a mixture of the complexing agent and a suitable solvent; (b) mixing; (c) adjusting the pH using a pharmaceutically acceptable buffer to a pH range of between about 7 and about
 9. (c) lyophilizing the mixture to obtain lyophilized particles.
 21. The method of claim 20, wherein the lyophilized particles are reconstituted in an effective amount of a pharmaceutically acceptable solution for injection into a human patient.
 22. The method of claim 20, wherein the statin is selected from the group consisting of lovastatin, simvastatin, mevastatin, atorvastatin, cerivastatin and rivastatin.
 23. The method of claim 20, wherein the complexing agent is a cyclodextrin.
 24. The method of claim 20, wherein the complexing agent comprises at least 13.5% of the formulation.
 25. The method of claim 20, wherein a solubilized statin concentration of at least about 3.32 mg/ml is obtained.
 26. A method of treatment comprising: (a) preparing lyophilized particles by adding a water insoluble statin to a mixture of a complexing agent and a suitable solvent and lyophilizing the mixture to obtain lyophilized particles; (b) reconstituting the lyophilized particles in a pharmaceutically acceptable solution for injection; and (c) administering a suitable quantity of the solution to provide an effective amount of statin to a human patient in need of treatment.
 27. The method of treatment of claim 26, wherein the statin is administered in an effective amount to lower the patient's lipid level, have an appropriate anti-inflammatory or other therapeutic effect. 